Pharmaceutical, chemical, biological, biochemical or biotech processes are, in increasing measure, performed in single-use containers (also referred to as disposables, or disposable bioreactors) as process containers. Such single-use containers can be, for example, flexible containers, e.g. bags, tubes or fermenters, or bioreactors. Bioreactors or fermenters frequently possess supply, and drain, lines, which can, for example, be embodied as tubes. In the supply, and drain, lines, also rigid tubular pieces can be inserted. After terminating a process, single-use containers can be disposed of. In this way, complex cleaning- and sterilization methods are avoided. Especially, through the use of single-use containers, the risk of cross contamination is prevented and, therewith, process safety is increased.
The processes performed in single-use containers proceed in a closed system, i.e. without connection to the environment outside the single-use containers. Since, frequently, sterile conditions are required, single-use container must be sterilized before introducing the process media. Frequently used for this purpose in biochemical, biological, biotechnological and pharmaceutical applications is gamma radiation. Also, in processes proceeding in a single-use fermenter or single-use reactor, the penetration of impurities, especially germs, from the environment into the interior of the process container must be prevented, in order not to degrade or corrupt the process flow.
In order to monitor or to check the processes, it can be necessary to measure physical or chemical, measured variables of the media contained in the process container. The measured variables to be monitored can be, for example, temperature, pH-value, cell density, optical transmission or a concentration of a chemical substance, for example, a certain kind of ion, a certain element or a certain compound, e.g. the content of dissolved oxygen or CO2. In biotechnological methods, important measured variables can include, moreover, so-called feeding material parameters, e.g. the glucose-, glutamate- or lactose content of the process medium, or metabolism parameters of the microorganisms applied in the method.
An opportunity for measuring at least some of these measured variables lies in the application of optical sensors. For example, sensorially active surfaces (technical term: optical sensor spots) capable of being read out optically can be arranged in the container. These can be accessed contactlessly externally through a window. For determining turbidity or cell density, likewise measurements can be performed externally through sending measuring radiation through a window or a transparent container wall and registering the radiation scattered and/or transmitted in the process medium.
Alternatively, or supplementally, to optical sensors, also electrochemical, especially potentiometric, sensors can be used, especially for determining the pH-value or an ion concentration in the process medium. Also amperometric sensors can be applied for determining the oxygen content or the CO2-content, as well as conductivity sensors, which work according to a conductive, or inductive, principle.
While in the case of optical sensors, at most, one sensorially active area, not, however, a measurement circuit or other components of the measuring transducer, come in contact with the process medium, it is, in the case of the named non-optical sensors, as a rule, required, to immerse the measuring transducer at least partially into the process medium and to lead out via wires a primary signal registered in the medium, or a signal derived therefrom, from the interior of the process container. Correspondingly, at least the part the non-optical sensors provided for introduction into the process container must be sterilized, just as the process container itself, while in the case of optical sensors, at most, the optically readable, sensorially active area must be sterilized.
In published international patent application WO 2009/071829 A2 and German Offenlegungsschrift DE 10 2006 005 533 A1, complex mechanical coupling systems are described, which enable sterile introduction of an externally sterilized sensor into a single-use container.
In order to avoid such complex coupling systems, the potentiometric probe can be installed via a connection fixedly in the process container, before the sterilization of the process container (for example, by irradiation with gamma radiation) and remain therein for the duration of storage and application. While the actual use time of the single-use container will amount to only few weeks, storage times can be in the order of magnitude of one or more years.
Electrochemical sensors, for example, potentiometric sensors as pH-glass electrodes or ion-selective electrodes, or amperometric sensors, e.g. for dissolved oxygen measurement, have sensitive membranes and one or more inner electrolytes, which, over the storage time of the sensor, can age, thus leading to a drift of the sensor and possibly even to degradation of the accuracy of measurement of the sensor.